Abstract:

Erythropoietin (Epo) is a glycoprotein hormone, produced primarily by the kidneys, that regulates the differentiation and proliferation of erythroid progenitor cells. Under normal conditions, Epo is present at the low concentrations required for maintenance replacement of aging cells. But stress situations such as anemia, blood loss, or hypoxia trigger the release of additional Epo which interacts with specific target-cell receptors to accelerate the release of reticulocytes. Recombinant erythropoetin has been cloned and is now being used to treat chronic renal failure.

Early Investigators

The first suggestion that erythropoietin had a humoral mechanism dates back to 1906 and the University of Paris – where, in 1906, Paul Carnot, professor of medicine, and his assistant Claude Deflandre, prepared a serum from rabbits with induced anemia. When this serum was injected into normal rabbits, the red cell count increased by 20 to 40 percent within two days.

As Jelkman (1986) points out these results could not be quantitatively reproduced. Probably because the blood donor rabbits, after a reported 30 ml blood loss, were not severely anemic.

In addition, the recipients received a relatively small serum volume (5 to 9 ml) and Carnot himself was aware of the fact that red blood cell counts, alone, are not a conclusive measure of erythropoietin activity.

Jelkman's article also reports on:

1. The serum experiments with animals done in Genoa by Gibelli (1911) that first confirmed and extended the Carnot and Deflandre observations.
    
2. Muller of Graz (1912) who found that the applications of serum from anemic guinea pigs prevented red cell reduction in bled mice.
    
3. Forster of Budapest (1924) who confirmed Muller's results using sera from rabbits exposed to hypobaric hypoxia.
    
4. Sandor (1932) who seems to have been the first to demonstrate reticulocytosis in rabbits produced by the administration of serum from hypoxic donors.
    
5. Feenders (1936) which failed to demonstrate any erythropoietic activity in plasma.

Further evidence for the humoral regulation of erythropoiesia was furnished by Reismann (1950) who observed erythrocytic activity in the bone marrow of parabiotic rat partners when one was normoxic, and the other breathed gas at lowered oxygen tension.

In 1953, Erslev reported a successful modification of the Carnot/Deflandre experiment by demonstrating significant reticulocytosis in rabbits infused with large volumes (100-2200 ml) of plasma from severely anemic rabbits (hematocrit <20%).

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